Severe jaundice causes chronic post-kernicteric encephalopathy, sensori-neural hearing loss (SNHL), and auditory neuropathy (AN) in infants. The American Academy of Pediatrics (AAP) guidelines for treatment to prevent bilirubin-induced neurotoxicity are based on measures of total serum bilirubin, but the utility of this indicator lacks evidence: it has high sensitivity but low specificity for bilirubin-induced neurotoxicity, so it often triggers unwarranted aggressive treatment. The Joint Committee on Infant Hearing (JCIH) recommends audiological evaluations in infants with total serum bilirubin levels at which exchange transfusion is indicated by AAP guidelines, but this recommendation also lacks evidence. This study will focus on unbound bilirubin, which has been shown by the Principal Investigator and his colleagues to be a better predictor of auditory dysfunction in premature infants than total serum bilirubin. The goal of the proposed research is to establish the usefulness of unbound bilirubin as a more sensitive and specific predictor of bilirubin-induced auditory toxicity in late preterm and term infants with severe jaundice (total serum bilirubin level = 20 mg/dl or level at which exchange transfusion is indicated). Because the prevalence of severe jaundice is low in the USA, an international collaborative study is required, that includes infants from India, where the prevalence of severe jaundice is high, and technologic expertise to measure unbound bilirubin that is available in the USA. Experienced investigators from academic institutions in India and the USA with common interests and complementary roles will collaborate to enroll 100 infants = 34 weeks gestational age with severe jaundice over two year period. Each participating center will provide clinical and laboratory data, following AAP guidelines for intervention and JCIH recommendations for auditory evaluations. Evaluations for auditory toxicity will be performed at each center by experienced audiologists, blinded to unbound bilirubin levels, at three different time periods: 1) time of hyperbilirubinemia 2) 2 months corrected age and 3) 9 months corrected age. The unbound bilirubin will be measured by the peroxidase method using an FDA approved UB analyzer in Rochester. Rigorous standardization across centers and protocols to monitor sample transport are in place. Regression analysis will be performed to evaluate the strength of association between unbound bilirubin and auditory toxicity. Receiver operating characteristic curves will be used to compare sensitivity and specificity for bilirubin-induced auditory toxicity of unbound bilirubin, bilirubin:albumin ratio, and total serum bilirubin. The findings of this study will lay the foundation for follow-up studies to evaluate the usefulness of unbound bilirubin for predicting chronic postkernicteric encephalopathy, and other long-term outcomes related to auditory toxicity such as language delay and central auditory processing disorder. The ultimate goal will be to reduce: 1) jaundice related morbidity, 2) unnecessary hospital admissions and associated costs, 3) unnecessary exchange transfusions and associated complications, 4) unnecessary auditory evaluations, and 5) parental anxiety and emotional stress. PUBLIC HEALTH RELEVANCE: Severe neonatal jaundice and associated morbidities is a global public health problem. American Academy of Pediatrics guidelines for treatment and Joint Committee on Infant Hearing recommendations for auditory evaluations lack evidence and are based on measures of total serum bilirubin, which have poor specificity for bilirubin-induced neurotoxicity. This clinical project to be performed in India and USA by experienced investigators will examine the usefulness of unbound bilirubin as a predictor of auditory toxicity in a diverse population of infants with severe jaundice. If unbound bilirubin is a better predictor than total serum bilirubin, it will greatly improve identification of severely jaundiced infants who are at risk for neurotoxicity and in need of phototherapy or exchange transfusion. This improved identification has ramifications for public health globally as it will help decrease: 1) jaundice related morbidity and mortality, 2) hospital admissions for intervention therapy, 3) unnecessary exchange transfusions that may be associated with complications, 4) unnecessary and costly auditory evaluations, and 5) parental anxiety and emotional stress.